Anti-neutrophil cytoplasmic autoantibodies (ANCA) are sensitive and specific serological markers of systemic necrotizing vasculitis, including Wegener's granulomatosis, microscopic polyangitis, Churg-Strauss syndrome and renal limited necrotizing glomerulonephritis. In vitro and in vivo evidence suggest that ANCA may participate in the pathogenic process. The long-term objectives of this proposal are to extend the knowledge of the clinical, pathologic, immunological and genetic characteristics of ANCA associated disease, and to elucidate the basic immunobiology, immunogenics, and pathogenesis of the ANCA autoimmune response and ANCA-associated diseases. The goal of Aim 1 is to elucidate the clinical, pathologic, serologic, and genetic characteristics of ANCA-associated diseases in a cohort of over 250 patients. It is hypothesized that: 1) ANCA are useful in monitoring disease activity, including patients with end-stage renal disease; 2) ANCA correlated with the pathologic activity; and 3) the ANCA autoimmune response is associated with restricted MHC class II genotype. The second Aim will investigate the origin, evolution, epitope specificity and immunogenics of the ANCA immune response. It is hypothesized that: 1) the ANCA autoimmune response is directed against a limited number of immunodominant epitopes; 2) ANCA production results from the expression of limited combinations of VDJ genes; 3) precursor B cells clones that react with DNA and MPO can be selectively expanded by antigen stimulation to produce either anti-MPO or anti-DNA autoantibodies; and 4) transgenic mice with anti-potentially pathogenic anti-MPO antibodies will sustain tolerance by down regulating the transgenic clone or will develop potentially pathogenic anti-MPO antibodies. . The final aim will explore the pathogenesis of ANCA-associated vasculitis, based on the hypothesis that ANCA are pathogenic, using an autoimmune strain of mice SCG/Kg and humanized SCID mice. It is postulated that: 1) in the vasculitic environment, ANCA cytokines and chemokines modify neutrophil apoptosis thus altering the balance of neutrophil clearance and neutrophil-mediated injury; 2) the ANCA antigens proteinase 3 and elastase, induce endothelial cell apoptosis; and 3) neutrophil and endothelial apoptosis are involved in the pathogenesis of vasculitis.